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Anti-malarial activity of a non-piperidine library of next-generation quinoline methanols

Milner, E and McCalmont, W and Bhonsle, J and Caridha, D and Cobar, J and Gardner, S and Gerena, L and Goodine, D and Lanteri, C and Melendez, V and Roncal, N and Sousa, J and Wipf, P and Dow, GS (2010) Anti-malarial activity of a non-piperidine library of next-generation quinoline methanols. Malaria Journal, 9 (1).

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Background. The clinical utility for mefloquine has been eroded due to its association with adverse neurological effects. Better-tolerated alternatives are required. The objective of the present study was the identification of lead compounds that are as effective as mefloquine, but exhibit physiochemical properties likely to render them less susceptible to passage across the blood-brain barrier. Methods. A library of drug-like non-piperidine analogs of mefloquine was synthesized. These compounds are diverse in structure and physiochemical properties. They were screened in appropriate in vitro assays and evaluated in terms of their potential as lead compounds. The correlation of specific structural attributes and physiochemical properties with activity was assessed. Results. The most potent analogs were low molecular weight unconjugated secondary amines with no heteroatoms in their side-chains. However, these compounds were more metabolically labile and permeable than mefloquine. In terms of physiochemical properties, lower polar surface area, lower molecular weight, more freely rotatable bonds and fewer H-bond acceptors were associated with greater potency. There was no such relationship between activity and LogP, LogD or the number of hydrogen bond donors (HBDs). The addition of an H-bond donor to the side-chain yielded a series of active diamines, which were as metabolically stable as mefloquine but showed reduced permeability. Conclusions. A drug-like library of non-piperidine analogs of mefloquine was synthesized. From amongst this library an active lead series of less permeable, but metabolically stable, diamines was identified. © 2010 Milner et al; licensee BioMed Central Ltd.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Milner, E
McCalmont, W
Bhonsle, J
Caridha, D
Cobar, J
Gardner, S
Gerena, L
Goodine, D
Lanteri, C
Melendez, V
Roncal, N
Sousa, J
Wipf, Ppwipf@pitt.eduPWIPF
Dow, GS
Date: 16 March 2010
Date Type: Publication
Journal or Publication Title: Malaria Journal
Volume: 9
Number: 1
DOI or Unique Handle: 10.1186/1475-2875-9-51
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Refereed: Yes
MeSH Headings: Antimalarials--pharmacokinetics; Antimalarials--pharmacology; Drug Discovery; Hypoxanthine; Mefloquine--pharmacology; Mefloquine--toxicity; Methanol--pharmacokinetics; Methanol--pharmacology; Permeability; Plasmodium falciparum--drug effects; Quinolines--pharmacokinetics; Quinolines--pharmacology
Other ID: NLM PMC2833169
PubMed Central ID: PMC2833169
PubMed ID: 20149249
Date Deposited: 07 Jun 2013 20:47
Last Modified: 20 Sep 2022 13:15


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